NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report.

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.

FACS analysis of Stat3/5 signaling reveals sensitivity to G-CSF and IL-6 as a significant prognostic factor in pediatric AML: a Children's Oncology Group report.

Signal transducer and activator of transcription 3 (Stat3) and Stat5 are critical signaling intermediates that promote survival in myeloid leukemias. We examined Stat3 and Stat5 activation patterns in resting and ligand-stimulated primary samples from pediatric patients with acute myeloid leukemia. Phosphorylated Stats were measured by FACS before and after stimulation with increasing doses of granulocyte-colony stimulating factor or IL-6. We also measured positive and negative regulators of Stat signaling, and we compared the variation in multiple parameters to identify biologic relationships. Levels of constitutively phosphorylated Stats were variable and did not correlate with survival. In terms of induced phospho-Stats, 15 of 139 specimens (11%) phosphorylated Stat3 in response to moderate doses of both granulocyte-colony stimulating factor and IL-6. Compared with groups that were resistant to 1 or both ligands, this pattern of dual sensitivity was associated with a superior outcome, with a 5-year event-free survival of 79% (P = .049) and 5-year overall survival of 100% (P = .006). This study provides important and novel insights into the biology of Stat3 and Stat5 signaling in acute myeloid leukemia. Patterns of ligand sensitivity may be valuable for improving risk identification, and for developing new agents for individualized therapy.

Comparable survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation.

BACKGROUND: We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML). PROCEDURES: Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children's Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006. RESULTS: Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43% ± 9%), MRD (46% ± 14%), or URD (50% ± 14%), P = 0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group = chemotherapy); MRD HR 1.08, P = 0.76; URD HR 1.13, P = 0.67] despite lower relapse risk with URD HCT (HR = 0.43, P = 0.01). CONCLUSIONS: Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.

Proactive enteral tube feeding in pediatric patients undergoing chemotherapy.

BACKGROUND: To determine feasibility and safety of proactive enteral tube feeding (ETF) in pediatric oncology patients. METHODS: Pediatric patients with newly diagnosed brain tumors, myeloid leukemia or high-risk solid tumors were eligible. Subjects agreeing to start ETF before cycle 2 chemotherapy were considered proactive participants (PPs). Those who declined could enroll as chart collection receiving nutritional standard of care. Nutritional status was assessed using standard anthropometric measurements. Episodes of infection and toxicity related to ETF were documented from diagnosis to end of therapy. A descriptive comparison between PPs and controls was conducted. RESULTS: One hundred four eligible patients were identified; 69 enrolled (20 PPs and 49 controls). At diagnosis, 17% of all subjects were underweight and 26% overweight. Barriers to enrollment included physician, subject and/or family refusal, and inability to initiate ETF prior to cycle 2 of chemotherapy. Toxicity of ETF was minimal, but higher percentage of subjects in the proactive group had episodes of infection than controls. Thirty-nine percent of controls eventually started ETF and were twice as likely to receive parenteral nutrition. PPs experienced less weight loss at ETF initiation than controls receiving ETF and were the only group to demonstrate improved nutritional status at end of study. CONCLUSIONS: Proactive ETF is feasible in children with cancer and results in improved nutritional status at end of therapy. Episodes of infection in this study are concerning; therefore, a larger randomized trial is required to further delineate infectious risks and toxicities that may be mitigated by improved nutritional status.

BIRC5 (survivin) splice variant expression correlates with refractory disease and poor outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group.

BACKGROUND: The inhibitor-of-apoptosis protein survivin, encoded by BIRC5, regulates apoptosis, cell division and proliferation. Several survivin splice variants have been described however, the prognostic significance of their expression has not been well defined in pediatric acute myeloid leukemia (AML). PROCEDURE: Quantitative expression analyses of BIRC5 mRNA (n = 306) and survivin transcript splice variants (n = 90) were performed on diagnostic bone marrow samples from children with de novo AML treated on the clinical trials CCG-2961 and AAML03P1, then correlated with disease characteristics and clinical outcome. RESULTS: Total BIRC5 expression did not correlate with clinical outcome. Fragment length analysis and sequencing of the entire BIRC5 transcript demonstrated three splice variants. The most prominent product, wild-type survivin, was expressed in all samples tested. Two minor transcripts were present in 90 patients treated on CCG-2961; survivin-2B and a novel variant, survivin-ΔEx2, characterized by deletion of BIRC5 exon II. A high 2B/ΔEx2 expression ratio (≥1) correlated with increased diagnostic WBC count, monocytic phenotype, +8 cytogenetics, lower complete remission (45% [n = 10] vs. 88% [n = 59], P < 0.001) and higher induction failure rates (23% [n = 5] vs. 3% [n = 2], P = 0.009). Consistent with this poor induction response, patients with a 2B/ΔEx2 ratio ≥1 had inferior 5-year survival rates (OS 36% vs. 60%, P = 0.011; EFS 23% vs. 53% at 5 years, P = 0.001) and appear to have increased relapse risk (P = 0.056). Subset analyses suggest that relative over-expression of 2B, rather than under-expression of ΔEx2 determines clinical response. CONCLUSIONS: High survivin-2B/ΔEx2 ratios are associated with refractory disease and inferior survival in childhood AML. Survivin splice variant expression warrants prospective evaluation in clinical trials.

Differences in outcomes of newly diagnosed acute myeloid leukemia for adolescent/young adult and younger patients: a report from the Children's Oncology Group.

BACKGROUND: Studies comparing survival of adolescent and young adult (AYA) patients to that of younger patients with newly diagnosed acute myeloid leukemia (AML) have yielded conflicting results. In order to more accurately characterize relative survival and other outcomes of AYA patients, a cross-study analysis was conducted using data from recent trials conducted by the Children's Cancer Group (CCG) and Children's Oncology Group (COG). METHODS: Data were combined from the CCG-2891, CCG-2941, CCG-2961, and AAML03P1 trials. The data set included 1840 patients, comprising 238 AYA and 1602 younger patients. RESULTS: Overall survival was not significantly different in the 2 groups (AYA, 49% ± 7% versus younger, 54% ± 3% (± 2 standard errors), P = .058). Relapse was lower in AYA patients (30% ± 7% versus 41% ± 3%, P = .002), but treatment-related mortality (TRM) was higher (25% ± 6% versus 12% ± 2%, P < .001). After adjustment for other factors, older age remained strongly associated with TRM (hazard ratio = 2.30, 95% CI = 1.59-3.33, P < .001). Infection accounted for the excess TRM in AYA patients. CONCLUSIONS: Survival in AYA and younger patients with newly diagnosed AML is similar; however, older patients are at higher risk for TRM. More effective strategies for preventing mortality from infection in AYA patients are needed.

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

IL-2 is a natural, T cell-derived cytokine that stimulates the cytotoxic functions of T and natural killer cells. IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (N = 905) and summary data from a sixth RCT (N = 550). Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR < 1 indicating treatment benefit. Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; P = .74) or overall survival (HR = 1.08; P = .39). Analyses including the sixth RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, P = .52; overall survival HR = 1.06; P = .46). No significant heterogeneity was found between the trials. Prespecified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy. We conclude that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.

Outcome of pediatric patients with acute myeloid leukemia (AML) and -5/5q- abnormalities from five pediatric AML treatment protocols: a report from the Children's Oncology Group.

BACKGROUND: Abnormalities of chromosome 5q (-5/5q-) are associated with poor prognosis in adults with acute myeloid leukemia (AML). However, there are no large studies on outcomes of children with -5/5q- AML. To determine the disease correlates of this group, we retrospectively analyzed cytogenetic data from five studies of childhood AML. PROCEDURE: Data from patients whose cytogenetic clones included -5/5q-, with the exception of those with acute promyelocytic leukemia or Down syndrome, were included. RESULTS: Of the 2,240 patients with cytogenetic data available, 26 (1.2%) had -5 or 5q-. A significant number of these patients were age 11-21 (61.5%, P = 0.031) and had M0 morphology compared with patients without -5/5q- (24.0% vs. 2.8%, P < 0.001). Twenty-two of the 26 patients had a complete remission (CR) response to induction chemotherapy. The 5-year overall survival (OS) from the time of diagnosis for the -5/5q- patients was significantly lower than for patients without -5/5q- (27 ± 17% vs. 50 ± 2%, P = 0.027). Similarly, from induction CR, patients with -5/5q- had significantly worse disease free survival, OS and relapse risk than those without this abnormality (27 ± 19% vs. 46 ± 2%, P = 0.035, 32 ± 20% vs. 57 ± 2%, P = 0.025, 68 ± 21% vs. 45 ± 2%, P = 0.01, respectively). CONCLUSIONS: Pediatric patients with AML and -5/5q- had a very poor outcome. These findings support the need for new or novel therapies for these patients.

Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML.

KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).

Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group.

BACKGROUND: Extramedullary leukemia (EML) is common in pediatric acute myeloid leukemia (AML) and occurs as leukemia cells within the cerebrospinal fluid (CSF) or as a solid tumor (myeloid sarcoma-MS). The effect of MS on survival is unknown. METHODS: Patients on CCG protocols 2861, 2891, 2941, and 2961 being treated for AML with intensive-timing chemotherapy were classified for the presence of EML (CSF leukemia, CNS-MS, orbital-MS, or non-CNS MS). CSF leukemia was classified as CNS3 (>5 WBC in the CSF with blasts) and non-CSF leukemia as CNS1/2 (<5 WBC in the CSF with or without blasts). Characteristics and outcomes of these patients were compared. RESULTS: Of the 1,459 total patients, 1,206 (82%) had no EML, 154 (11%) had CSF leukemia, 19 (1%) had CNS-MS, 23 (2%) had orbital-MS, and 57 (4%) had non-CNS MS. The CR rate was significantly higher in patients with orbital-MS and CNS-MS than in those with non-MS and non-CNS MS (96% and 95% vs. 78% and 78%, P = 0.034). Patients with orbital-MS and CNS-MS had significantly higher overall survival than patients with non-CNS MS (92% and 73% vs. 38%, P < 0.001), CNS3 patients (92% and 73% vs. 51, P < 0.001), and CNS1/2 patients (92% and 73% vs. 50%, P < 0.001). Patients with orbital-MS had a significantly lower relapse rate. CONCLUSION: Patients with MS involving orbital and CNS sites had a significantly better survival than patients with non-CNS MS, with CSF leukemia, or with no EML.

Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML.

Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management.

Soluble interleukin-2 receptor α activation in a Children's Oncology Group randomized trial of interleukin-2 therapy for pediatric acute myeloid leukemia.

PURPOSE: To assess associations of soluble IL-2 receptor alpha (sIL-2rα) concentration with outcomes in pediatric acute myeloid leukemia (AML) in a phase 3 trial of IL-2 therapy. PROCEDURES: We randomized 289 children with AML in first remission after intensive chemotherapy to receive IL-2 infused on days 0-3 and 8-17 (IL-2 group) or no further therapy (AML control group). We measured sequential serum sIL-2rα concentrations in both groups before, during and after therapy in both groups and in reference controls without AML. RESULTS: Before treatment, mean sIL-2rα concentrations were similar in the IL-2 group and AML controls, but significantly higher than in reference controls. Both AML groups experienced reduction in sIL-2rα concentration after chemotherapy. Thereafter in the IL-2 group, mean sIL-2rα concentration increased from 2,669 pg/ml before IL-2 to 15,534 pg/ml on day 4 (P < 0.001) and 10,585 pg/ml on day 18 (P < 0.001). In the control group sIL-2rα concentration did not change after 28 days of follow-up. Five-year disease-free survival (DFS) was 51% in the IL-2 group and 58% in the controls (P = 0.489) and overall survival was 70% and 73%, respectively (P = 0.727). CONCLUSION: SIL-2rα concentration was elevated in AML at diagnosis and tended to normalize after chemotherapy. IL-2 infusion significantly increased sIL-2rα concentration, but did not improve DFS or survival in pediatric AML. Furthermore, sIL-2rα concentration was not predictive of outcome before, during or after treatment for AML.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma. METHODS: We performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. RESULTS: Twenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS: Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00031590.

Structural and numerical variation of FLT3/ITD in pediatric AML.

FLT3 internal tandem duplication (FLT3/ITD) is a common somatic mutation in acute myeloid leukemia (AML) with significant variation in the position, length, and number of duplications of the FLT3 gene. We evaluated these physical characteristics in FLT3/ITD-positive patients who were treated on CCG-2941/2961 and correlated them with clinical outcome. Fiftynine of 77 FLT3/ITD-positive patients (77%) had a single ITD, 16 (21%) had 2 ITDs, and 2 (3%) had 3 ITDs. The length of the duplicated region varied from 6 to 51 amino acids, and in all cases amino acid residues Y591-Y597 were duplicated. Structural analysis demonstrated that Y591-Y597 encodes the switch and zipper regions of the juxtamembrane domain of FLT3. In addition, 24 of 77 patients (31%) had duplication of the critical STAT5 docking sites Y589/591. Patients with longer ITDs had a worse relapse-free survival (19% vs 51%, P = .035), while the presence of more than 1 ITD was not clinically significant. Physical characteristics including the length of FLT3/ITD may influence FLT3 activation state by altering its structure and may impact response to therapy.

The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: a Children's Oncology Group study.

BACKGROUND: The presence of central nervous system (CNS) disease in pediatric acute myeloid leukemia (AML) is often thought to confer a worse prognosis. This study examined the outcome of children with AML who had CNS disease at diagnosis. METHODS: Patients enrolled on Children's Cancer Group protocols 2861, 2891, 2941, and 2961 being treated for de novo AML were classified for the presence of CNS disease at diagnosis as CNS1 (<5 WBC in the CSF without blasts), CNS2 (<5 WBC in the CSF with blasts), or CNS3 (> or =5 WBC in the CSF with blasts). CNS disease at diagnosis was then analyzed regarding patient characteristics and outcome. RESULTS: There was an incidence of CNS disease (i.e., CNS3 status) of 11% in the 1,459 patients analyzed in this study. The risk factors found are young age, high white cell count, hepatomegaly or splenomegaly at diagnosis, M4 subtype, chromosome 16 abnormalities, and hyperdiploid cytogenetics. There were no significant differences in overall survival, event free survival, or remission rates between the groups; however, a significant difference was seen between the CNS1 and CNS3 groups in disease free survival and isolated CNS relapse risk. CONCLUSIONS: Patients with CNS disease at diagnosis have similar survival to those without CNS disease, although they have an increased incidence of isolated CNS relapse. Patients with CNS disease at diagnosis may warrant more aggressive CNS directed therapy.

FAS promoter polymorphism: outcome of childhood acute myeloid leukemia. A children's oncology group report.

PURPOSE: FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down-regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine transition in the FAS promoter region (position -1377) is thought to reduce stimulatory protein 1 transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at -1,377 bp significantly attenuates transcription factor stimulatory protein 1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might affect outcome of childhood AML therapy. EXPERIMENTAL DESIGN: Four hundred forty-four children treated for de novo AML on a uniform protocol were genotyped for FAS 1377. RESULTS: There were no significant differences in overall survival, event-free survival, treatment-related mortality, or relapse rate between patients with FAS 1377GG genotype versus 1377GA/1377AA genotypes. CONCLUSIONS: FAS 1377 genotype does not alter outcome of de novo AML in children.

Bone-marrow relapse in paediatric acute lymphoblastic leukaemia.

Marrow relapse is the major obstacle to cure for 10-15% of young patients with acute lymphoblastic leukaemia (ALL). Recent investigations into the biology of minimal residual disease indicate that many early relapses derive from residual cells present at first diagnosis, but some late relapses might represent new mutations in leukaemic cells not eliminated by conventional therapy. Treatment of marrow relapse involves higher doses and more intensive schedules of the drugs used for initial therapy with or without haemopoietic stem cell transplantation. In most reports, transplantation is better than continuation chemotherapy in early marrow relapse, but its role in later relapse is less clear. Current therapy cures 10% of patients with early marrow relapses and 50% of those with late relapses, but outcomes have changed little in the past two decades. Understanding the molecular biology of ALL underlies development of improved risk stratification and new therapies. Although better drugs are needed, introduction of new agents into clinical trials in paediatric disease has been difficult. Innovative trial designs and use of valid surrogate endpoints may expedite this process.

Central nervous system juvenile xanthogranuloma with malignant transformation.

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that typically manifests in the skin. Here, we describe a patient with JXG diffusely involving the central nervous system (CNS), whose disease responded to therapy but subsequently underwent dissemination to the peritoneum and bone marrow. Repeat biopsy at dissemination revealed pleomorphic histiocytes with tetraploidy, suggesting evolution to a clonal histiocytic neoplasm. Despite further chemotherapy, the patient died of disease progression. This case highlights the clinical and pathological heterogeneity of JXG and the difficulty of treating multi-focal CNS disease.

Outcomes in childhood AML in the absence of transplantation in first remission--Children's Cancer Group (CCG) studies 2891 and CCG 213.

BACKGROUND: The majority of childhood acute myeloid leukemia (AML) patients lack a matched-related bone marrow transplant (BMT) donor in first remission. PROCEDURE: Disease-free survival (DFS), overall survival (OS), relapse-free survival (RFS), and post-relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent-to-treat, ITT) or who received (as-treated, AT) only chemotherapy intensification. RESULTS: Outcomes at 8 years post-induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P 12 months portends a much better OS for patients who relapse. Post-relapse treatment included BMT in 47% of patients. CONCLUSIONS: OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post-relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race.